The dietary treatment of inborn errors of metabolism.

In the course of evolution, man has acquired digestive enzymes that split complex food components to simpler, absorbable molecules, biosynthetic enzymes that reform complex body components and degradative enzymes that catabolize these components. Each enzyme is a protein and its biosynthesis is under genetic control. Mutation of the gene coded for the enzyme, or for one polypeptide where an enzyme molecule consists of more than one polypeptide chain, can lead to inactivity of that enzyme which, in turn, often leads to serious disease. These diseases are the inborn errors of metabolism. The specific carrier mechanisms that transport molecules across membranes (e.g. in the jejunum, renal tubules, etc.) are also based on specific proteins, the biosynthesis of each being under genetic control; mutation of these genes leads to a second group of inborn errors of metabolism affecting, e.g., absorption from the gut. Primary alactasia, the inherited absence of intestinal lactase (p-galactosidase; EC 3.2.1.23), leads to inability to hydrolyse lactose, which therefore enters the colon and is fermented by the gut flora (Holzel, 1962; Prader & Auricchio, 1965; Dahlqvist & Asp, 1975). The infant fails to gain weight (lactose is an important part of the newborn infant’s total energy intake) and has diarrhoea with frothy, acid stools. The situation is life-threatening unless the lactose of the milk is replaced by some other carbohydrate, e.g. glucose, in an artificial mixture which otherwise resembles milk. In galactosaemia the enzyme galactoseI-phosphate uridylyltransferase (EC 2.7.7.10) is absent or inactive. This causes accumulation of the enzyme’s normal substrate, galactose-I-phosphate and, by ‘back-up’, of galactose. Galactose-Iphosphate is toxic: untreated patients usually die, and the survivors suffer damage to the liver (cirrhosis), the brain (mental retardation), the kidneys (renal tubular dysfunction) and the eyes (cataracts). Treatment is with a diet free from galactose (Woolf, 1962; Hsia, 1969; Segal, 1972; Kalckar, Kinoshita & Donnell, 1973). This is usually effective if started in earliest infancy but some infants show an incomplete response, the result, it is believed, of irreversible damage by galactoseI-phosphate that accumulated in utero. Perhaps the best-known of the treatable inborn errors of metabolism is phenylketonuria (PKU). The amino acid phenylalanine is normally oxidized through a series of steps, each catalysed by a specific enzyme, to urea, carbon dioxide and water. The first step is oxidation of phenylalanine to tyrosine by molecular oxygen in the presence of phenylalanine 4-hydroxylase (EC I . I ~ . ~ . I ) , an